DESCRIPTION: (Applicant's Abstract) Recently, a consensus has been generated linking the neuropeptide, galanin to cholinergic basal forebrain function in normal and pathologic states including AD (see 12, 18, 72). Numerous experimental studies have shown that galanin inhibits acetylcholine (ACh) levels in vitro (25) and impairs working memory in rats (18, 19, 32). In AD, we and others have shown that galaninergic system undergoes a hyperplasticic response upon remaining CBF neurons (12,72) which may alter ACh neurotransmission. cholinergic deficits in AD (20, 101) occur early in the disease process (89) and correlate with both the severity (102) and duration (102) of this disorder. Moreover, a vast animal and clinical literature connects CBF neurons, which innervate the cortex and hippocampus (59), to memory function (2,4). During the previous funding period we demonstrated a dramatic species difference in the chemical signature of GAL-innervation within the CBF between humans and experimental animals including monkeys (9,48). These observations indicate that animal models of GAL-based CBF interactions do not accurately mimic the human condition. Thus, only investigations examining the human GAL/CBF system may truly be relevant towards elucidating the mechanism(s) underlying the interaction between GAL and ACh within the CBF. Thus, studies of the GAL/ACh interaction within the human CBF will provide greater understanding of the pathologic process(es) affecting cholinergic cell dysfunction in AD. The purpose of this renewal is to continue our ongoing investigation of the pathophysiologic changes underlying galanin plasticity with the CFG and their relation to cognitive dysfunction in AD. We will test the hypothesis that GAL remodeling is associated with an increase in the number of GAL mRNA-expressing neurons in AD. Alternatively, we will test the hypothesis that there is an increase in GAL mRNA synthesis per neuron within the CBF in AD. We will determine whether galanin hypertrophy is associated with an increase in the number of receptor sites (Bmax) or a change in GAL affinity (binding; KD) within the CFG in AD. We will also test the hypothesis that there is a regional specificity of changes in GAL receptor binding within the CBF in AD. We will test the hypothesis that galanin hyperexpression is associated with cognitive impairment among individuals with AD. These studies will use in situ hybridization, receptor pharmacology, radioimmunoassay and neuropsychological testing procedures. The data generated from these studies will provide new information concerning the unique galanin basal forebrain remodeling response in AD. Furthermore, these data may suggest avenues for pharmacological therapies aimed at retarding intellectual deterioration in AD.